Several are the diseases that affect the retina (retinal diseases) including age related macular degeneration, retinitis pigmentosa, diabetic retinopathy, macular edema and other inherited retinal degenerations, uveitis, retinal detachment, and eye cancers. The retina is the light sensitive portion of the eye, and is a complex tissue containing specialized photoreceptor cells, the cones and the rods. The photoreceptors connect to a network of nerve cells for the local processing of visual information, which is sent to the brain for obtaining a visual image. The rods are mostly located away from the centre of the eye in the retinal periphery. The highest concentration of cones is found at the center of the retina, the macula, which is necessary for visual acuity.
Under the retina is located the choroid. The retinal pigment epithelium (RPE) is a monolayer of pigmented cells situated between the neuroretina and the choroids. The RPE is the pigmented cell layer just outside the neurosensory retina that nourishes retinal visual cells. RPE cells protect, support, and feed the light sensitive retina. The dysfunction, disruption and/or loss of these RPE cells play a critical role in the development of the vision loss. Thus, RPE cells are often the first cells to degenerate or suffer damage as a result of a traumatizing event or condition.
Another structure of the eye being of great importance in many of the retinal diseases is the blood-retinal barrier (BRB), also called hemato-retinal barrier. The BRB is constituted by the inner blood-retinal barrier and the external blood-retinal barrier. Inner blood-retinal barrier is formed by the tight junctions of endothelial cells. External blood-retinal barrier is constituted by the RPE, which cells are also connected by tight junctions. Tight junctions between RPE cells are essential to control the transport of liquid and soluble compounds through the BRB, as well as to avoid any toxics into the retina. Therefore, RPE is a key component of the external blood-retinal barrier to assure retina integrity. The two most frequent retinal diseases that are due to an impairment of the external BRB thus resulting in retinal edema are diabetic macular edema and age-related macular degeneration. In addition, alteration of the BRB occurs also in a wide variety of ocular situations, such as uveitis, trauma, intraocular surgery, vascular retinopathies, hereditary dystrophies, etc. (Cunha-Vaz et al., “The Blood-Retinal Barrier in Retinal Disease”, European Ophthalmic Review—2009, Vol. No. 3, pp.: 105-108).
Several approaches to identify the causes of many of the retinal diseases have been performed. One of them is based on the performance of proteomic analysis of vitreous humour. The vitreous humour is the clear gel that fills the space between the lens and the retina of the eyeball of humans and other vertebrates. It is often referred to as the vitreous body or simply “the vitreous”.
The proteomic analysis by differential gel electrophoresis of the vitreous has been applied for the characterization of the proteome in Proliferative Diabetic Retinopathy and in other ocular pathologies such as Diabetic Macular Edema. Examples of this are found in Ramirez et al., “Proteomic Analysis of Human Vitreous Fluid by DIGE: a New Strategy for Identifying Potential Candidates in the Pathogenesis of Proliferative Diabetic Retinopathy”, Diabetologia 2007, Vol. 50, pp.: 1294-1303; in Gao et al., “Characterization of Vitreous Proteome in Diabetes without Diabetic Retinopathy and Diabetes with Proliferative Diabetic Retinopahty”, Journal of Proteome Research—2008, vol. 7, pp. 2516-2525; and in Hernández et al. “New pathogenic candidates for diabetic macular edema detected by proteomic analysis”, Diabetes Care 2010; 33:e92.
Nowadays most of the treatments of the diseases affecting the retina are implemented in advanced stages of the diseases rather than to arrest or prevent their development. Thus, in the particular case of macular edema or in some retinopathies (proliferative or non-proliferative diabetic retinopathy) the treatment is usually based on laser photocoagulation, vitrectomy and corticosteroids intravitreal injections. All these treatments are encouraged in late-stages of these diseases, that is, there are no effective early treatments. Moreover, they imply many side effects (pain, inflammation, hemorrhage, etc.) and a high ratio of failures is in addition observed.
It is worth mentioning that all these diseases are of great impact, not only because they lead to blindness or to altered vision impeding people to develop normal life (working, walking, driving, etc.), but also because they are generally linked with highly prevalent disorders, such as diabetes mellitus (in particular the type 2), and age-related macular degeneration (AMD). The relation with high prevalent disorders makes in turn all these retinal disorders of common presence in the society, thus representing a challenge for the health institutions.
Other therapeutic approaches are based on the injection of compounds able to block the vascular endothelial growth factor (VEGF), such as the antibody Ranibizumab (trade name Lucentis), which has been approved to treat the “wet” (also known as exudative or neovascular) type of age-related macular degeneration (AMD), a common form of age-related vision loss. The antibody is intravitreally injected once a month. The most common side effects associated to this treatment in clinical trials were conjunctive hemorrhage, eye pain, vitreous floaters, increased intraocular pressure, and intraocular inflammation.
Thus, there is a need of additional therapeutically approaches to face all the diseases in which retina is affected, in particular those diseases wherein RPE and BRB are compromised.